Background
The course of disease in interstitial lung diseases (ILD), including rheumatoid arthritis-associated interstitial lung disease (RA-ILD), is known to be highly variable. Predicting the survival of an individual patient with ILD is challenging [
1]. Several factors have, however, been proposed to predict disease progression and survival i.e. physiological, radiological and histopathological characteristics, as well as demographic variables such as age and gender [
2]. Some factors reflecting the severity of the rheumatoid arthritis (RA) have also been associated with worse survival, e.g. baseline pain [
3], disease activity score [
4] and health-assessment questionnaire score [
3,
5].
There are now several indexes which combine single factors into a multifaceted scoring system and these have proved beneficial in estimating prognosis. These models have, however, focused mainly on idiopathic pulmonary fibrosis (IPF) and some of the earliest models were rather cumbersome and therefore never achieved any widespread clinical acceptance [
6]. A composite physiologic index (CPI) displayed some important advantages over the older models, since it contained only pulmonary function test (PFT) and gas transfer values but omitted radiological scoring or exercise testing [
7]. The subsequently developed GAP model combines gender (G), age (A) and two lung physiology variables (P), i.e. forced vital capacity (FVC) and diffusion capacity to carbon monoxide (DLCO), into a multidimensional index and staging system with three stages (I-III) proposing 1-year mortality of 6, 16 and 39% [
8]. This GAP model has also been utilized in the prognosis of other chronic ILDs in addition to IPF. The modified model was named as ILD-GAP, with the assumption that patients with connective tissue disease-related ILDs (CTD-ILD) enjoyed a better survival than those suffering from IPF [
9]. The survival of patients with RA-ILD has been shown to be as poor as in IPF patients [
10], at least in those cases with usual interstitial pneumonia (UIP) which is the most common subtype in RA-ILD and unlike the situation in the other CTD-ILDs [
11]. Thus, since it is mainly UIP-typed, RA-ILD follows a distinctive disease course from the other CTD-ILDs and it remains unclear which of the prognostic indexes, GAP or ILD-GAP, would be better suited for RA-ILD. There are some reports of the benefits of using the CPI score, GAP and ILD-GAP staging systems in patients with IPF and systemic sclerosis-associated ILD [
12‐
14]. However, as far as we are aware, neither CPI nor GAP/ILD-GAP have been previously investigated in patients with RA-ILD, if one excludes the subjects in the original ILD-GAP publication, which did include some RA-ILD patients in their CTD-ILD/idiopathic nonspecific interstitial pneumonia (iNSIP) group of 326 patients.
The aims of this study were to investigate the applicability of CPI, GAP and ILD-GAP scores for predicting the prognosis of the patients with RA-ILD treated in Kuopio University Hospital (KUH), in Eastern Finland, during the years 2000–2014. In addition, we examined the association between individual PFT and demographic factors with the survival of the patients.
Discussion
In this present study, we applied the GAP and the ILD-GAP scores in a cohort consisting of 59 patients with RA-ILD subdivided into GAP / ILD-GAP stages I and II. Both GAP systems showed significant differences in age, gender, FVC, FEV1, DLCO and CPI-score, which is understandable since GAP / ILD-GAP are mainly composed of the above-mentioned components. The median survival of the patients categorized into GAP / ILD-GAP II groups was significantly shorter than those in the GAP / ILD-GAP I group. The CPI score was an independent predictor of mortality similarly as GAP / ILD-GAP scores, age, baseline DLCO and hospitalization due respiratory reasons. However, after adjustment for age, only the CPI score and DLCO remained as statistically significant predictors. In addition to the Cox model, the applicability of GAP and ILD-GAP was tested using two different statistical methods. Both the GAP and the ILD-GAP methods provided relatively good estimates of mortality. Interestingly, the GAP index was more accurate at predicting 2-year and 3-year mortality, whereas ILD-GAP predicted 1-year mortality more precisely.
To our knowledge, only a few previous studies have investigated GAP or ILD-GAP scores in patients with CTD-ILD but some analyses of IPF have been published. In Korean IPF patients, the GAP score produced accurate 1-year, but not 3-year, mortality estimates [
13]. In another study of IPF patients, the GAP staging was found to be useful for evaluating the IPF severity, revealing statistically significant differences in survival in different GAP stages [
12]. On the other hand, the ILD-GAP index displayed poor applicability for the predicted 1-year mortality in systemic sclerosis-associated ILD patients [
14].
In this study, the observed 1-year mortality was 0 in stage I and 8.3% in stage II patients. Predicted 1-year mortality using the ILD-GAP was 3.1 and 8.8% in stages I and II, respectively. Thus, the accuracy of ILD-GAP was good at predicting 1-year mortality but the observed 2-year mortality in stage I patients was much higher than predicted by the ILD-GAP model i.e. the GAP model was more accurate at that time point. The ILD-GAP prediction also underestimated the 3-year mortality of stage I patients, which was observed to be 17.6 and therefore was even slightly higher than the value predicted by GAP. Both of the indexes, however, fitted within the confidence interval of the observed mortality. Since the accuracy of GAP and ILD-GAP in predicting annual mortality in our study was variable at different points, it remains unclear whether the GAP or ILD-GAP index is better suited in predicting mortality of patients with RA-ILD. The ILD-GAP was originally developed in a study protocol including all kinds of ILDs without taking into account the fact that the prognosis and course of disease is variable in the different types CTD-ILDs [
19,
20]. In some earlier studies, the survival of RA-ILD patients has been reported as being as poor as in IPF [
3,
21], whereas that of other types of CTD-ILD has appeared to be better [
10,
19,
22]. Furthermore, various radiological or histological patterns in certain CTD may behave differently, e.g. patients with RA-UIP have been shown to have a shorter survival than those with other CTD-ILDs [
23,
24]. Therefore, it can be debated whether the ILD-GAP, which is merely a simple subtraction from the GAP score assuming a better survival in CTD-ILDs, is valid in all CTD-ILDs.
The significance of PFT has been widely recognized when evaluating ILD severity and the risk of death. In fibrotic subtypes of IIPs, it has been postulated that pulmonary physiology is an even stronger predictor of survival than the histopathologic pattern [
25] and that in patients with IPF, changes in FVC % predicted and DLCO % predicted have been shown to associate with mortality [
26,
27]. Moreover, a prospective follow-up study of 29 RA-ILD patients demonstrated that in over 30% of cases, a degree of radiological progression was observed, and this progression was strongly associated with a reduced DLCO [
28].
In a recent retrospective study of 48 biopsy-confirmed RA-ILD patients, the baseline DLCO was detected as an important risk factor for death in a univariate model similarly as found here [
29]. In that particular study, however, DLCO lost its statistical significance in the multivariate model, when only age and the presence of fibrosis remained significant [
29]. Another study of 82 RA-ILD patients diagnosed without biopsy found that baseline DLCO was associated with survival in the bivariate analysis, and DLCO remained statistically significant also in the multivariate analysis [
30]. In a very recent study, a relatively large cohort of 137 RA-ILD patients was retrospectively evaluated, with univariate, multivariate and also longitudinal methods being used to analyze the predictors of mortality [
31]. In that study a baseline DLCO value of 10% lower than the mean value and DLCO decline of 10% or more at any time after baseline were identified as significant predictors of mortality [
31]. Furthermore, in the study of Song et al. [
32] which examined 84 RA-UIP patients, the hazard ratio of baseline DLCO did not reach statistical significance, but the change of DLCO was significant in both univariate and multivariate models. Unfortunately, we were not able to investigate the change in DLCO over time because of missing follow-up data due to the retrospective nature of our study protocol. In addition, multivariate models could not be applied because of the small number of patients in our study. However, we observed that the significant positive result of DLCO in univariate analysis remained after adjusting for age. Overall, the results of DLCO in our study support the previous findings of the suitability of DLCO in the disease severity evaluation of RA-ILD.
Baseline FVC was not found to be an independent predictor of mortality in our study, a finding which is at odds with some previous studies. A recent study showed that the lower baseline FVC (10% or more under mean value) and a 10% decline in FVC were both associated with an increased death hazard in various multivariate models [
31]. Furthermore, another investigation demonstrated that the baseline FVC, as well as the FVC change over time, were significant predictors of mortality in patients with RA-UIP [
32]. There may be two possible explanations why the significance of FVC in our study differs from these other publications. Firstly, in our study, the mean baseline FVC was relatively high, i.e. 84.8, being within the normal limits in the majority of the patients whereas the corresponding value in the study of Solomon et al. was 69.3, and that from Song et al. was 75.1 [
31,
32]. Our finding refers that the patients had been diagnosed earlier with more preserved lung functions. Secondly, our study includes 59 patients, thus being relatively small, compared to those other studies of 84 and 137 patients. On the other hand, the results of the study of Kim et al., which included 84 patients with RA-ILD who had lower mean baseline of FVC values than in our study (66 ± 25 in RA-UIP, 70 ± 20 in non-UIP) did not actually find FVC to be a predictor of death, i.e. similar to our results [
23]. Even though FVC alone was not a strong predictor of mortality in our study, it is one factor included in CPI and GAP / ILD-GAP scores, all of which showed significant positive results in our univariate analyses. Our finding supports that the use of multifaceted scoring systems for evaluating the prognosis of the patients with RA-ILD may be beneficial.
Acknowledgements
The authors wish to thank Ewen MacDonald for providing assistance with the language, Tiina Laitinen for assistance in the search of missing PFT data and Juuso Tamminen for helping editing Fig.
1.